SE444935B - NEW PROCEDURE FOR PREPARATION OF 7- (SUBSTITUTED) -AMINO-3-SUBSTITUTED-THIOMETHYL-DELTA? 723-CEFEM-4-CARBOXYLIC ACID - Google Patents

Description

7905899-6 'kanoyl or the like, or cephalosporin C or a derivative thereof is used as starting material. However, the cited publications describe that even according to the cited method it is preferable to carry out the reaction in water or a mixture of water and an organic solvent in the vicinity of neutrality.

In the case of a method in which a cephalosporin C derivative is used as a starting material, British Patent Specification 1,400,804 and Japanese patent application Kokai (effenfliggjera) 9s.oss / 1e, for example, state that the conversion into 3-position is carried out. in water or a mixture of water and an organic solvent in the presence of a halide or inorganic salt of a Group I or II metal in the Periodic Table, such as KI, NaI-cerz, Baiz, Nacl, NH4ci, Beclz, Mgclz or similar. However, the method in which an acylated cephalosporanic acid, cephalosporin C or its derivatives are used as starting material involves a complicated reaction, since the amino group in the 7-position must be acylated or an acylated starting material must be used, and the acyl group must be removed by iminohalogenation, imino lining. , hydrolysis or the like after the 3-position conversion. In this reaction, the 3-position conversion itself is carried out with a thiol or its salt in a mixture of water and an organic solvent under the above-mentioned preferred conditions, and the yield is generally 60 to 80 percent.

Against the background of the above, the present inventors have carried out extensive research with the aim of developing a method for simple industrial conversion of the group in the 3-position with a thiol compound or its salt in high yield, and it has unexpectedly been found that satisfactory results are obtained when the reaction is carried out in an organic solvent in the presence of a protic acid or another-Lewis acid or Lewis acid complex compound other than boron trifluoride and its complex compounds.

An object of the invention is to provide a process for the preparation of a 7- (substituted) amino-3-substituted-thiomethyl-A3-cephem-4-carboxylic acid or a derivative with respect to its carboxyl group or a salt thereof which is important as an intermediate for a cephalosporin compound from a cephalosporanic acid or a derivative with respect to its carboxyl group, in high yield and high purity by means of an industrial simple operation.

Other objects and advantages of the invention will become apparent from the following description.

According to the invention there is provided a process for the preparation of a 7- (substituted) amino-3-substituted-thiomethyl-β-cephem-4-carboxylic acid represented by the general formula (1). ßl. Wherein R 1 is a hydrogen atom or a C 1-4 alkoxy group, R 2 is an amino group or a group represented by the formula H 3 I 2 I 2 4 5 1 | C = C-NH-, where R3, R and R, which may be identical or fine, are different, are hydrogen or organic groups not participating in. The H6 'reaction, or of the formula 7 / Ö = iii-f' wherein RG and R7, as R may be identical or different, are hydrogen or organic groups not participating in the reaction, and R8 is a thiol compound residue, a derivative with respect to the carboxyl group of the above-mentioned carboxylic acid or a salt thereof, which consists in allowing a cephalosporanic acid represented by the general formula (II) 'H2, Y1 - N \ CH2X' (II ) O ~.

COOH where R1 and R2 have the meaning given above, X is an unsubstituted or substituted acyloxy or carhamoyloxy group, 2 Y is> S or jSa0, or a derivative with respect to the carboxyl group of the cephalosporanic acid or a salt thereof, react with a thiol compound represented by the general formula (III), R 5 - sn (111) wherein R 8 has the meaning given above, or a salt of the thiol compound, in an organic solvent in the presence of a protic acid or a Lewis acid or Lewis acid complex compound other than boron trifluoride and its complex compounds.

You can not only use a compound where> Y is 2 S but also a chemically stable compound where Ä Y is 2 S ë> 0 as starting material. In the latter case, a reduction reaction of> S å O takes place due to the presence of a protic acid, or another Lewis acid or Lewis acid complex compound other than boron trifluoride and its complex compounds, whereby a compound is obtained there).

As examples of C 1-4 alkoxy group for R1 in the above general formulas (I) and (II) may be mentioned methoxy, ethoxy, propoxy, butoxy and the like.

As examples of unsubstituted or substituted acyloxy or carbamoyloxy groups for X in the general formula (II) may be mentioned C 1-8 alkanoyloxy groups, for example formyloxy, acetoxy, propionyloxy, butyryloxy and the like; alkenoyloxy groups, C 3-8 for example acryloyloxy and the like; C7-11 aroyloxy groups, for example benzoyloxy, naphthoyloxy, and the like; C8-9 aralkanoyloxy groups, for example phenylacetoxy, phenylpropionyloxy and the like; carbamoyloxy groups; and the like, of which Cl_8-7905899-6 acyloxy groups and carbamoyloxy groups are preferred. Examples of the substituent in substituted acyloxy or carbamoylloxy groups are known substituents for acyloxy or carbamoyloxy groups, such as halogen, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-8 acyl, C 1-8 acylo ¿8-acylamino, hydroxyl, carboxyl, sulfamoyl, carbamoyl, cyano, carboxy-C 1-4 alkoxycarbamoyloxy, benzoylcarbamoyl, carboxy-C 1-4 alkoxysulfamoyl, and the like. In the general formulas (I) and (II), R is an amino group or a group represented by the formula 123 PP I 'BC = C _ mi .- or \ C = 1 .; ... _ _ '' Ra / 15 R1 / ”IR in Formula Bg s H1, in C = () ~ I fl â- can also be described as R, CK =? -N- as an isomer, and the latter is also included in the invention .

As organic groups for R3, R4, Rs, R6 and R7 which do not participate in the reaction, one can use those known in the art, and examples of these are unsubstituted or substituted aliphatic groups, alicyclic groups , aromatic groups, araliphatic groups, heterocyclic groups, acyl groups and the like. More particularly, the following groups may be exemplified: (1) Aliphatic group: alkyl groups, for example, methyl, ethyl, propyl, butyl, isobutyl, pentyl and the like; and alkenyl groups, for example vinyl, propenyl, butenyl and the like. (2) Alicyclic group: cycloalkyl groups, for example cyclopentyl, cyclohexyl, cycloheptyl and the like; and cycloalkenyl groups, for example cyclopentenyl, cyclohexenyl and the like. (3) Aromatic group: aryl groups, for example phenyl, naphthyl and the like. 7 (4) Araliphatic group: aralkyl groups, for example benzyl, phenethyl and the like. 7. (5) Heterocyclic group: heterocyclic groups containing one or more heteroatoms (oxygen, nitrogen and sulfur) in any combination in any position in the molecule, for example pyrrolidyl, piperazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl , thiazolyl, pyridyl, imidazolyl, quinolyl, benzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like. (6) Acyl group: acyl groups derived from organic carboxylic acids. Examples of organic carboxylic acids include aliphatic carboxylic acids; alicyclic carboxylic acids; alicycloaliphatic carboxylic acids; araliphatic carboxylic acids, aromatic oxialiphatic carboxylic acids, aromatic thioaliphatic carboxylic acids, heterocyclic ring-substituted aliphatic carboxylic acids, heterocyclic oxyaliphatic carboxylic acids, and heterocyclic direct carboxylic aromatic hydrocarbons acid or sulfur atom; organic carboxylic acids in which an aromatic ring, an aliphatic group or an alicyclic group is attached to a carbonyl group via an oxygen, nitrogen or sulfur atom; aromatic carboxylic acids; and heterocyclic carboxylic acids.

Examples of the above-mentioned aliphatic carboxylic acids are formic acid, acetic acid, propionic acid, butanoic acid, isobutanoic acid, pentanoic acid, methoxyacetic acid, methylthioacetic acid, acrylic acid, crotonic acid and the like. As examples of the above-mentioned alicyclic carboxylic acids may be mentioned cyclohexanoic acid and the like, and as examples of the above-mentioned alicycloaliphatic carboxylic acids may be mentioned cyclopentane-acetic acid, cyclohexane-acetic acid, cyclohexane-propionic acid, cyclohexadiene-acetic acid. As the aromatic group in the above-mentioned organic carboxylic acids may be mentioned phenyl, naphthyl and the like, and as the heterocyclic group may be mentioned residues of heterocyclic compounds containing at least one heteroatom in the ring, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, oxazole, isooxazole-thiadiazole, oxadiazole, thiatriazole, oxatriazole, tetrazole, benzoxazole, benzofuran and the like.

Each of the groups constituting the above-mentioned organic carboxylic acid may be further substituted by a substituent, for example a halogen atom, a hydroxyl group, a protected hydroxyl group, a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-4 acyl group, a nitro group, an amino group, a protected amino group, a mercapto group, a protected mercapto group, a carboxyl group, a protected carboxyl group or the like.

As protecting groups in the above-mentioned hydroxyl-, protected-position, or -acyl, and R-amino-, protected-mercapto- and protected-carboxyl groups, those which will be mentioned below with respect to the substituents in the R8 group can be used.

R 3, R 4 and R 5 may be identical or different and are preferably hydrogen, C 1-5 alkyl, C 2-4 alkenyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, aralkyl, a heterocyclic group containing 0, N and S_ individually or in any combination in any 6 and R 7 may be identical or different and are preferably hydrogen, C 1-5 alkyl, C 2-4 alkenyl, C 5-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, aralkyl, a heterocyclic group containing O, N and S individually or in combination in any position, or acyl.

Examples of derivatives with respect to the carboxyl group of the Å compounds represented by the general formulas (I) and (II) may be mentioned commonly known derivatives in the field of penicillin and cephalosporin, of penicillin and cephalosporin, for example the following compounds: oa) Esters: all esters which do not affect the reaction at all include, for example, substituted or unsubstituted alkyl esters, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tern-butyl ester, methoxymethyl ester, ethoxymethyl ester, phenoxymethyl ester, methylthiomethyl 6 ester, methylthioethyl ester, phenylthiomethyl ester, dimethylaminoethyl ester) diethylaminoethyl ester, morpholinoethyl ester, piperidinoethyl ester, acetylmethyl ester, phenacyl ester, toluoylmethyl ester, 4-nitrophenacyl ester acetoxymethylethyl} pivaloylmethyl ester methoxycarbonylmethyl ester, methanesulfonylethyl ester, toluene ~ sulfonylethyl ester, bromomethyl ester, iodine tyl ester, trichlorethyl ester, cyanomethyl ester, tenoyl methyl ester, phthalimidomethyl ester and the like; cycloalkyl esters such as cyclohexyl ester, cycloheptyl ester and the like; alkenyl esters such as propenyl ester, allyl ester, 3-butenyl ester and the like; alkynyl esters such as propynyl ester and the like; substituted or unsubstituted aryl esters such as phenyl ester, tolyl ester, xylyl esters; naphthyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, p-methoxyphenyl ester, trichlorophenyl ester, pentachlorophenyl ester, p-methanesulfonylphenyl ester and the like; substituted or unsubstituted aralkyl esters such as benzyl ester, phenethyl ester, p-chlorobenzyl ester, p-nitrobenzyl ester} p-methoxybenzyl ester, 3,5-dimethoxybenzyl ester, diphenylmethyl ester, bis (4-methoxyphenyl) methyl ester, 3,5-di-tert. -butyl-4-hydroxybenzyl ester, trityl ester and the like; indanyl ester; phthalidyl ester, other esters formed from a carboxylic acid and thioalcohol, tetrahydrofuranol, 1-cyclopropylethanol, 1-phenyl-3-methyl-5-yyrazolone, 3-hydroxypyridine, 2-hydroxypyridine-1-oxide or the like, which may be optionally substituted with a halogen atom, a nitro group, an alkoxy group or the like; and esters formed by the reaction of a carboxylic acid with methoxyacetylene, ethoxyacetylene, tert-butylethynyldimethylamine, ethylethynyldiethylamine, or N-ethyl-5-phenylisoxazolium-3-sulfonic acid salt. b) Anhydrides of the carboxyl group with N-hydroxy succinic acid amide, N-hydroxyphthalic acid amide, dimethylhydroxylamine, diethylhydroxylamine, 1-hydroxypiperidine, oxime or the like. c) Amides: all acid amides, N-substituted acid amides, and N, N-di-substituted acid amides include, for example, N-alkyl acid amides, such as N-methyl acid amide, N-ethyl acid amide and the like; N-aryl acid amides such as N-phenyl acid amide and the like; N, N-dialkylic acid amides such as N, N-dimethylacidamide, N, N-diethyl-acidamide, N-ethyl-N-methylacidamide and the like; and acid amides with imidazole, 4-substituted imidazole, triazolopyridone and the like.

The salt in the term "a compound of the general formula (I) or (II), or a derivative with respect to its carboxyl group or a salt thereof" as used herein is intended to include both salt at the acid group (for example a carboxyl group ) And salt at the basic group (for example an amino group). Examples of salts in the acidic group are salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; salts with nitrogen-containing organic bases such as triethylamine, diethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N, N-dimethylaniline and the like.

Examples of salts in the basic group are salts with mineral acids, such as hydrochloric acid, sulfuric acid and the like; salts with organic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts with sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and the like. These salts may have been previously prepared and isolated or may be prepared in the reaction system.

Hydrates of the starting compounds and intended compounds mentioned above are also included in the invention.

R8 in the general formulas (I) and (III) represent residues of thiol compounds known in the field of cephalosporin, and include, for example, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, thiocarbamoyl, alkoxythiocar bonyl, aryloxythiocarbonyl, cycloalkyloxythiocarbonyl, amidino and heterocyclic groups. More specifically, examples include C 1-8 alkyl, such as methyl, ethyl, propyl, butyl, isobutyl and the like; C 5-7 cycloalkyl, such as cyclohexyl, cycloheptyl and the like; and C 7-9 alkyl; such as benzyl, phenethyl and the like; aryl, such as phenyl, naphthyl and the like; acyl, such as acetyl, propionyl, butyryl, benzoyl, naphthoyl, cyclopentanecarbonyl, cyclohexanecarbonyl, furoyl, tenoyl, isothiazolylcarbonyl, isoxazolylcarbonyl, thiadiazolylcarbonyl, triazolylcarbonyl and _ _.....-_.......-- -.._- - V Ȓ90sa99-6% 10 similar; thiocarbamoyl such as thiocarbamoyl, N-methylthiocarbamoyl, N, N-diethylthiocarbamoyl, 1-piperidinothiocarbonyl, 1-morpholinothiocarbonyl, 4-methyl-1-piperazinylthiocarbonyl and the like; C 1-4 alkoxytiocarbonyl, such as methoxythiocarbonyl, ethoxythiocarbonyl; propoxythiocarbonyl, butoxythiocarbonyl and the like; aryloxythiocarbonyl) such as phenoxythiocarbonyl and the like; C 1-7 cycloalkyloxythiocarbonyl such as cyclohexyloxythiocarbonyl and the like; amidino, such as amidino) N-methylamidino, N, N'-methylamidino, and the like; and heterocyclic groups such as oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imiazolyl, pyrazolyl, pyridyl, pyrazinyl} pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, indolyl, indazolyl, triazolyl, triazolyl, triazoliaz, triazinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridyl, purinyl, pyridin-1-oxide-2-yl, pyridazin-1-oxide-6-yl, tetrazolopyridazinyl, tetrazolopyrimidinyl, thiazolopyridazinyl, thiazolopyridazinyl, triazolopyridazinyl. As the heterocyclic group for R 8, nitrogen-containing heterocyclic groups containing at least one nitrogen atom with or without the oxygen or sulfur atom are preferred.

Furthermore, the groups for R 8 may be substituted with at least one substituent, such as halogen, C 1-4 alkyl, phenyl, hydroxyl, mercapto, C 1-4 alkoxy, C 1-4 alkylthio, nitro, cyano, cyano-C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkyl-C 1-8 -amino, C 1-4 acyl, C 1-8 acyloxy, carboxyl, carbamoyl, amino-C 1-4 alkyl, N-C 1-5 alkylamino-C 1-4 alkyl, N, N-di-C 1-4 alkylamino-C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, carboxyl-C 1-4 alkyl , sulfo, sulfamoyl-C 1-4 alkyl, snlfamoyl, carbamoyl-C 1-4 alkyl, C 2-4 alkenyl, carbamoyl-C 2-4 alkenyl, N-C 1-4 alkylcarbamoyl, N, N-di-C 1-4 alkylcarbamoyl, rC 1-8 acyl-C 1-4 alkyl, N-C 1-4 alkyl, N-C 1-4 alkyl di-C 1-4 alkylcarbamoyl-C 1-4 alkyl, and the like, and among these substituents the hydroxyl, mercapto, amino and carboxyl groups may be protected with a suitable protecting group commonly used in the field of penicillin or cephalosporin. The protecting group for the amino group includes all groups which can be used as common amino protecting groups, for example trichloroethoxycarbonyl, tribromoethoxycarbonyl, ben- '7-syloxycarbonyl, p-toluenesulfonyl, p-nitrobenzyloxycarbonyl, o-bromophenylphenylsulphenylsulphenyl trifluoroacetyl, formyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, pyridin-1-oxide-2-ylmethyl -pyridylmethoxycarbonyl, 2-furyloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 1-cyclopropylethoxycarbonyl; phthaloyl, succinyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like, which are easily eliminable acyl groups; other easily eliminable groups such as trityl, 2-nitrophenylthio, 2,4-dinitrophenylthio, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, 1-methocycarbonyl-2 propylidene, 1-ethoxycarbonyl-2-propylidene, 3-ethoxycarbonyl-2-butylidene, 1-acetyl-2-propylidene, 1-benzoyl-2-propylidene, 1- [N (2-methoxyphenyl) carbamoyl] -2-propylidene 1- [N- (4-methoxyphenyl) carbamoyl] -2-propylidene; 2-ethoxycarbonylcyclohexylidene, 2Eethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; and di- or tri-alkylsilyl.

The protecting groups for the hydroxyl and mercapto groups include all groups which can usually be used as protecting groups for hydroxyl and mercapto groups, for example easily eliminable acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyloxycarbonyl, - (phenylazo) benzyloxycarbonyl, 4- (4-methoxyphenylazo) benzyloxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2,2-tricycarbonyl 2,2-tribromoethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-cyclopropylethoxycarbonyl, 3-quinolyloxycarbonyl, trifluoroacetyl and the like; benzyl, trityl; methoxymethyl; 2-nitrophenylthio, 2,4-dinitrophenylthio and the like.

The protecting group for the carboxyl group includes all groups which can be commonly used as carboxyl protecting groups, for example ester-forming groups such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, benzyl, diphenylmethyl, triphenylmethyl, p-nitrobenzyl, p-methoxobenzyl, p-methoxyl , benzoylmethyl, acetylmethyl, p-nitrobenzoylmethyl, p-bromo-benzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichlorethyl, 1,1-dimethyl-2-propynyl, acetoxymethyl, propionyloxymethyl, pivaloyloxyl; , 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, succinimidomethyl, 1-cyclopropylethyl, methylsulphenylmethyl, phenylsulphenylmethyl, methylthiomethyl, phenylthiomethyl, dimethylaminomethyl, quinolin-1-oxide-2-ylmethyl, pyridine -1-oxide-2-ylmethyl, di- (p-methoxyphenylkmethyl and the like; silyl residues of silyl compounds listed in Japanese patent application Kokai (published) 7073/71 and Dutch patent application 7105259 (already publicly available), such as dimethyldichlorosilane non-metallic travel of non-metallic compounds disclosed in German Offenlegungsschrift 2,0§2,925, such as titanium tetrachloride; and similar.

Salts of the thiol compound represented by the general formula (III) may be in the form of basic salt or acid salt depending on the type of R8 and include both the base and acid salts. For examples of the salts, the above description of the salt of the compounds represented by the general formulas (I) and (II) is applicable. As the material for forming the salt of the thiol compound, one can use the materials for forming the salts of the compounds represented by the general formulas (I) and (II).

As examples of protic acids, pyrophosphoric acid, pyrosulfuric acid, sulfuric acids, sulfonic acids and superacids can be mentioned. As used herein, the term "superacid" refers to acids that are stronger than 100% sulfuric acid and comprise some of the sulfonic acids and sulfuric acids. di-) sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and the like and aryl (mono-, di- or tri-) sulfonic acids such as benzenesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid and the like The superacids include perchloric acid, Wmagic acid "(FSO3H- SbF5) Ä ~ FSO3H ~ AsF5ï CF¿SO3H-SbF5, HZSO4-SO3 and the like. Lewis acids other than boron trifluoride include, for example, zinc halides and tin halides, and more specifically include zinc chloride, zinc bromide, tin tetrachloride, tin tetrabromide and the like; The complex compounds of Lewis acids other than complex compounds of boron trifluoride include complex salts of the above Lewis acids other than boron trifluoride with dialkyl ethers such as diethyl ether, di-n-propyl ether, di-n-butyl ether and the like: complex salts of the aforementioned Lewis acids with amines such as ethylamine , n-propylamine, n-butylamine, triethanolamine, dimethylformamide and the like; complex salts of the aforementioned Lewis acids with fatty acids such as acetic acid, propionic acid and the like; complex salts of the aforementioned Lewis acids with nitriles, such as acetonitrile, propionitrile and the like; complex salts of the above Lewis acids with carboxylic acid esters such as methyl formate, ethyl formate, ethyl acetate and the like; and complex salts of the above Lewis acids with phenols such as phenol, (1- or 2-) naphthol and the like. The above sulfonic acids may be substituted with halogen atoms such as fluorine, chlorine, bromine and the like, carboxyl groups, sulfo groups, nitro groups, lower alkyl groups such as methyl, ethyl and the like or lower alkoxy groups such as methoxy, ethoxy and the like.

The compound represented by the general formula _,! e í '»~ få * - p. 1: 5' (Il) where 112 is u / c s fi; _ s, 'or> C = N _ R DE R? wherein R 3, R 4, R 5, R 6 and R 7 are synthesized by reacting 7-aminocephalosporanic acid with an aldehyde or a ketone in an inert solvent (in Japanese, denovan has the stated meaning the patent publication 28,913 / 69) and the compound represented by the general formula (II), wherein R 1 is a C 1-4 alkoxy group, can be synthesized by introducing the C 1-4 alkoxy group into the compound represented by the general formula (II), wherein R 1 is a hydrogen atom, in a manner known per se (Journal of ._ i _....._.___...._._.____..._._._.._._. _ i 79os399ëe, l4 synthetip organic Chemistry, Japan, 35, 563 - 574 41977), etc.).

As the organic solvent in the process of the invention, all organic solvents which do not adversely affect the reaction can be used, and nitriles, nitroalkanes, organic carboxylic acids, ketones, ethers and sulfolanes are preferred.

These solvents can be used in a mixture of two or more. The abovementioned nitriles include, for example, aliphatic nitriles, aliphatic dinitriles, aromatic nitriles, and heterocyclic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, isovaleronitrile, caproononitrile, caproonitrile, capro crotononitrile, lauronitrile, palmitonitrile, stearonitrile, acrylonitrile, malononitrile, succinonitrile, glutaronitrile, adiponitrile, benzonitrile, tolunitrile, cyanated benzyl, cinnamon-nitrile, naphthanitrile, cyanoanthonitrile. The nitroalkanes include nitromethane, nitroethane, nitropropane, nitrobutane, nitropentane, nitrohexane, nitroheptane, nitrooctane and the like.

The organic carboxylic acids include aliphatic saturated monocarboxylic acids and aliphatic saturated dicarboxylic acids, such as formic acid, acetic acid, propionic acid, lactic acid, isolactic acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid and the like. The ketones include aliphatic saturated ketones, aliphatic unsaturated ketones, alicyclic ketones, aromatic ketones, and heterocyclic ketones such as acetone, ethyl methyl ketone, methyl propyl ketone, isopropyl methyl ketone, butyl methyl ketone, isobutyl diethyl ketone methyl methone ketone, , cyclopentanone, cyclohexanone, acetophenone, propiophenone, butyrophenone, valerophenone, dibenzyl ketone; acetothienone, 2-acetofuron and the like. The ethers include aliphatic saturated ethers, aliphatic unsaturated ethers, aromatic, ethers and cyclic ethers such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, diisobutyl ether, methyl ethyl ether, methyl propyl ether, methyl isopropyl ether, methyl butyl ether, ethyl isobethyl ether, ethyl isobethyl ether, ethyl isobethyl ether ethyl butyl ether, ethyl isobutyl ether, ethylene glycol dimethyl ether, diallyl ether, methyl allyl ether, ethyl allyl ether, anisole, ethylene ethanol, dibenzyl ether, phenylbenzyl ether, tetrahydrofuran, tetrahydropyran, dioxane and the like.

The sulfolanes include sulfolane and the like. The organic solvent used in the invention may form a complex with said Lewis acid other than boron trifluoride, and this organic solvent complex with said Lewis acid other than boron trifluoride is also used as the organic solvent in the invention; The amount of the protic acid or Lewis acid or Lewis acid complex compound other than boron trifluoride and its complex compounds used may be at least one mole per mole of the compound represented by the general formula (II), or a derivative with respect to its carboxyl group or a salt thereof, and preferably at least 2 moles, especially 2 to 10 moles, per mole of the latter. When the complex compound is used, it can also be used as a solvent, and a mixture of two or more complex compounds can also be used. In general, it is desirable to vary the amount of protic acid or Lewis acid or complex compound of Lewis acid other than boron trifluoride and its complex compounds to control the rate of reaction depending on the type of solvent and thiol compound or its salt used. The amount of the thiol compound represented by the general formula (III) or its salt used is usually at least one mole per mole of the compound represented by the general formula (II) or a derivative with respect to its carboxyl group or a salt thereof, and preferably 1 to 1.5 moles per mole of the latter. When using as a starting material a compound where E Y is> S-à-O, the thiol compound or its salt is preferably used in an amount of 2 to 3 moles per mole of the starting material. Although no particular limitation applies to the reaction temperature, the reaction is usually carried out at a temperature of -200 to 80 ° C, and the reaction time is usually several minutes to several hours.

In the process of the invention, the following dehydrating agents may be added to the reaction system: phosphorus compounds such as. m ... V ..., ... ~ - ~ n _-.-.-- ~ v ~~ v --- --w- ~ '~~ _ .q fi -... rv-.sw -' ¿79o5s99- 6 'acetamide, g 16 as phosphorus pentachloride, polyphosphoric acid, phosphorus pentoxide, phosphorus trichloride, phosphorus oxychloride and the like; organic silyl compounds such as an N, O-bis (trimethylsilyl) -acetamide, trimethylsilyl-trimethylchlorosilane, dimethyldichlorosilane and the like; organic acid chlorides such as acetyl chloride, p-toluenesulfonyl chloride and the like; acid anhydrides such as acetic anhydride, trifluoroacetic anhydride} and the like {and inorganic compounds for drying such as anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous calcium sulfate, molecular sieves, calcium carbide and the like.

The above reaction conditions are not limiting and can be varied appropriately depending on the type of reactants and solvents to achieve the purpose. 3.

R 1 \\\ _> The protecting group ä // C = -ïU1 ~ or R Ef R 6 \ '° H7 / pen for the carboxyl group in the derivative with respect to the carboxyl- C = IJ-5 for R 2 in the general formula (I) and The protecting group of the compound represented by the general formula (I) can usually be removed by hydrolysis or treatment in a conventional manner to convert the protecting groups to an amino group resp. carboxyl group. In the case of some 3 ~ -'s.

R. R, \ _ \ '_ groups / c = C ~ HH- QCh / C - H ~ Up I s - 7; n RS. However, when R is used or when a certain post-treatment is used, the protecting group for the amino group is easily removed during the treatment to give a compound represented by the general formula (I) wherein R 2 is an amino group. In the case where the carboxyl group in the compound represented by the general formula (I) is protected with certain protecting groups or when a certain after-treatment is used, the protecting group is easily removed during the treatment for converting the protected carboxyl group to a carboxyl group to give a compound represented by the general formula (I). When R3, R4, R5, R6 and R7 are organic groups which do not participate in the reaction and which have a protected hydroxyl, amino, mercapto- or carboxyl group as a substituent, these groups can be transferred to the desired substituents by the resulting compound is subjected to elimination reaction in a conventional manner. The above-mentioned protecting group elimination reaction can be carried out without isolating the product obtained. The compound of the invention of the general formula (I) thus obtained can be isolated in a conventional manner.

The compound of the invention represented by the general formula (I) can be used directly as a starting material for acylation reaction, but it can be converted, if necessary, into highly pure 7- (substituted) -amino-3-substituted-thiomethyl-Åk cefem -4-carboxylic acid in high yield in a conventional manner.

The invention is further illustrated by the following non-limiting exemplary embodiments, and all temperatures are given in degrees Celsius.

Example 1 (1) In 27 ml of acetic acid, 2.72 grams of 7-aminocephalosporanic acid and 1.16 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended, and 5.76 grams of methanesulfonic acid was added to the suspension to form a solution. . This solution was allowed to react at 50 ° for 2.5 hours. After completion of the reaction, the mixture was cooled and gradually added to 27 ml of water under ice-cooling. Then the mixture was adjusted to a pH of 4.0 with 28% by weight of aqueous ammonia. The crystals thus precipitated were collected by filtration, washed with 5 ml of water and 5 ml of acetone in this order, and then dried to give 2.70 grams (yield 82.3 percent) of 7-amino-3- [5- ( 1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -A 3 -Cephem-4-carboxylic acid having a melting point of 224 ° to 226 ° (Sun.). 5-IR NMR (D 2 O + CF 3 CO 2 D) ppm values: 3.58 (2H, s, c 2 -H 2), 3.84 (3H, s, j: N-CH 3), 4.09 <2H, s, cs-cH 2), 4.91 (1H, d, J = 5 eps, ca-H), 5.05 (1H, a, J = 5 eps, C7-H).

Elemental analysis for C 10 H 11 N 6 O 3 S 2: Calculated (%) C, 35.59; H, 3.69: N, 25.6l. Found (%) C, 36.47; H, 3.72; N, 25, 21 (2) The same procedure as in (1) above was repeated, except that the methanesulfonic acid was replaced by other acids, the following results being obtained: 'Use Reaction Conditions. - (% ¥ ä temp. (C) time (tim.) Conc .sulfuric acid 6.57 50 1.5 84.5 Éšíššïârmetansul- '9'0 50 1 87.7 p-toluenesulfonic acid 10.3 50. .1, 78.5 Alfur sulfuric acid 3.5 50 _ l 76.2 -Fluorosulfuric acid 3.0 room temperature 1.5 84.3 (3) In (1) above was added an aqueous ammonium acetate solution (Q, 77 grams of ammonium acetate / 4 ml of water) and 3.3 ml of 12N hydrochloric acid to the reaction mixture, after completion of the reaction, and the resulting mixture was stirred at 150 for 2 hours, after which the crystals thus precipitated were collected by filtration, washed with two 5 ml portions of acetone, and then dried, 2.44 grams (67.0 percent yield) of 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Z-3-cephem-4-carboxylic acid> hydrochloride were obtained with a melting point of 184 ° to 1860 (Sun,) _. __..-_ ~. -_ .. w -_ .., ._..._ 7905899-6 19 IR (roar) cnflwæo 177o, ~ 171o_ NMR (D20 + CF3CO2D): Identical with standard sample.

Elemental analysis for C 12 OH 13 N 6 O 3 S 2 Cl: Calculated (%) C, 32.91; H, 3.59; N, 23.03 Found (%) C, 32.55; H, 3.48; N, 22.73 Example 2 In 80 ml of 0.1 N perchloric acid solution in acetic acid was dissolved 0.54 grams of 7-aminocephalosporanic acid and 0.25 grams of 5-mercapto-1-methyl-1H-tstrarol, and the solution was allowed to react at 50-55 ° in 2.5 hours.

After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 ml of water.

To the resulting aqueous solution was added dropwise concentrated aqueous ammonia under ice-cooling, after which the pH of the solution was adjusted to 3.5 and the solution was then stirred for 15 minutes.

The crystals thus precipitated were collected by filtration, washed with 2 ml of water and 3 ml of methanol in this order, and then dried to give 0.53 grams (yield 80.8 percent) of 7-amino-3- [5- (1 -methyl-1,2,3,4-tetrazolyl) -thiomethyl] -53-cephem-LL-carboxylic acid has a melting point of z24 ° 1-.111 22e ° (Sun.

The IR and NMR of the product were identical to those of the standard sample.

Example Gel 3 In 13.5 ml of acetic acid was dissolved 1.36 grams of 7-aminocephalosporanic acid and 0.58 grams of 5-mercapto-1-methyl-1H-tetrazole, and 3.9 grams of anhydrous tin tetrachloride were added to the suspension to form a solution. This solution was allowed to react at 50 ° for 1.5 hours, after which the solvent was removed by distillation under reduced pressure. To the residue was added 10 ml of water, and further 28% by weight of aqueous ammonia was added under ice-cooling to adjust the pH of the solution to 7.5. The crystals thus precipitated were collected by filtration, washed with 5 ml of water and 5 ml of acetone in this order, and then dried to give 1.28 grams (yield 78.0 percent) of chloride, and the the resulting mixture was allowed to react at 50 -4 hours. After completion of the reaction, the reaction mixture was diluted with 7-amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -α, 3-cephem-4-carboxylic acid.

Example 4 In 3 ml of acetic acid, 0.27 grams of 7-aminocephalosporanic acid and 0.2 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended, and 1.36 grams of anhydrous zinc chloride was added to the suspension to form a solution. . This solution was allowed to react at 500 for 4 hours and then diluted with 3 ml of water. The pH of the solution was adjusted to 3.8 with 28% by weight of aqueous ammonia under ice-cooling. The crystals thus precipitated were collected by filtration, washed with 2 ml of 0.1 N hydrochloric acid, 2 ml of water and 1 ml of acetone in this order, and then dried to give 0.26 grams (yield 79.2 percent) of 7-amino acid. 3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -153-cephem-4-carboxylic acid.

IR, NMR and melting point of the product were identical with the corresponding data for standard samples.

When the zinc chloride was replaced with 3.2 grams of zinc bromide, the yield was 77.3 percent. Example 5 1.36 grams of 7-aminocephalosporanic acid and 0.58 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 15 ml of acetic acid, and , 48 grams of methanesulfonic acid was added to the suspension to form a solution. To this solution was added 6.80 grams of anhydrous zinc-O. with 15 ml of water, after which the pH was adjusted to 3.8 with 28% by weight of aqueous ammonia under ice-cooling. The crystals thus precipitated were collected by filtration, washed with 10 ml of 0.1 N hydrochloric acid, 10 ml of water and 5 ml of acetone in this order, and then dried to give 1.35 grams (yield 82.3 percent). N-amino-s- [cyclin-methyl-1,2,3A-tetrazolyl) thiomethyl] -β-cephem-4-carboxylic acid, 1 IR, NHR and melting point of the product were identical with the corresponding data for standard samples.

Example 6 - 0.305 grams of p-toluenesulfonic acid salt of diphenylmethyl 7-aminocephalosporanate and 0.058 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 5 ml of acetic acid, and 0.45 grams of trifluoromethanesulfonic acid was added to the suspension to give of a solution.

This solution was allowed to react at 500 for 1.5 hours, after which the solvent was removed by distillation under reduced pressure.

To the resulting residue were added 2.5 ml of water and 2.5 ml of acetone, and the resulting mixture was stirred under ice-cooling for 30 minutes. Then 28% by weight of aqueous ammonia was added to adjust the pH to 4.0. The crystals thus precipitated were collected by filtration, washed with 3 ml of water and 3 ml of acetone in this order, and then dried to give 0.127 grams (yield 77.2 percent) of 7-amino-3- [5- (1-methyl) -1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid.

The IR, NMR and melting point of the product were identical with the corresponding data for standard samples.

Example 7 0.796 grams of sodium 7- (2-hydroxybenzylideneamino) cephalosporanate and 0.232 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 8 ml of acetic acid, and 1.80 grams of trifluoromethanesulfonic acid was added to the suspension to form a solution. This solution was allowed to react at room temperature for 3 hours. Under ice-cooling, 1 ml of water and 1.5 ml of 12 N hydrochloric acid were added to the reaction mixture, and the resulting mixture was stirred at room temperature for 2 hours. The crystals thus precipitated were collected by filtration, washed with two 1-ml portions of acetic acid and two 3-ml portions of acetone in this order, and then dried to give 0.503 grams (yield 69.0 percent) of 7-amino-3 - [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -β-cephem-4-carboxylic acid hydrochloride. ~ 79u5s99-6 I 722 IR, NMR and melting point of the product were identical with the corresponding data for standard samples.

Example gel 8 (1) 0.58 grams of trifluoromethanesulfonic acid was subsequently dropped into 6.8 ml of acetonitrile, and 0.58 grams of 5-mercapto-1-methyl-1H-tetrazole and 1.36 grams of 7-aminocephalosporanic acid were added to this order. to the solution so that a solution was formed. The resulting solution was heated to 30 °, at which temperature the reaction was carried out for 60 minutes. The reaction mixture was then cooled with ice, and 5.7 ml of water was added gradually. The pH of the solution was adjusted to 3.9 with 28% by weight of aqueous ammonia, and the solution was stirred at the same temperature for 2 hours. The crystals thus precipitated were collected by filtration, washed with two 1-ml portions of water and two 1-ml portions of acetone in this order, and then dried to give 1.5 g (yield 91.5 percent) of 7-amino-3 - [5- (1-methyl-1,2,3,4-tetrazolyl) -thiomethyl] -β-cephem-4-carboxylic acid.

The IR, NMR and melting point of the product were identical with the corresponding data for standard samples. (2) The same reaction as above was carried out, adding to the reaction mixture dropwise 0.84 ml of 12 N hydrochloric acid and 0.68 ml of water in this order under ice-cooling, after which the resulting mixture was stirred for 3 hours. The crystals thus precipitated were collected by filtration, washed with two 2-ml portions of acetonitrile and two 3-ml portions of acetone in this order, and then dried to give 1.64 grams (yield 90.0 percent) of 7-amino. -3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] ÅA3-cephem-4-carboxylic acid hydrochloride.

IR, NMR and melting point of the product were identical with the corresponding data for standard samples. (3) When acetonitrile in (1) above was replaced by propionitrile, the yield was 88.4%. 79osa99 ~ e 23 (4) When acetonitrile in (1) above was replaced with sulfolane, the yield was 89.6 percent. (5) When acetonitrile in (1) above was replaced with nitromethane, the yield was 84.3 percent. §§S92šl_2 _ 2 s 2.72 grams of 7-aminocephalosporanic acid and 1.16 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 27 ml of acetonitrile, and 9.75 grams of conc. sulfuric acid was gradually added under ice-cooling to form a solution. This solution was then allowed to react at 30 ° C for 1 hour, and the reaction mixture was cooled to 5 ° and then gradually added to 60 ml of water under ice-cooling.

The pH of the solution was adjusted to 3.7 with 28% by weight of aqueous ammonia, and further 30 ml of water were added.

The resulting solution was stirred at the same temperature for 1 hour.

The crystals thus precipitated were collected by filtration, washed with two 15 ml portions of water and three 10 ml portions of acetone in this order, and then dried to give 2.93 grams (yield 89.3 percent). amino-3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid. 1 R, NMR and melting point of the product were identical with the corresponding data for standard samples.

Example 10 1.36 grams of 7-aminocephalosporanic acid and 0.60 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 6.8 ml of acetonitrile, and 3.50 grams of conc. sulfuric acid was gradually added under ice-cooling to form a solution. This solution was allowed to react at 300 for 75 minutes, after which 1.7 ml of 12 N hydrochloric acid and 2.0 ml of water were added dropwise in this order while maintaining the same temperature. The resulting mixture was cooled to 150 and allowed to stand at 100 ° to 15 ° for 2.5 hours to precipitate crystals.

The precipitated crystals were collected by filtration, washed with two 5-ml portions of acetonitrile and two-ml portions of acetone in this order, and then dried to give 1.51 grams (yield 83.0 percent) of 7-amino-3 - [5- (1,2-methyl-1,2,3,4-tetrazolyl) thiomethyl] -β-cephem-4-carboxylic acid hydrochloride.

The IR, NMR and melting point of the product were identical with the corresponding data for standard samples.

Example 11, 1.36 grams of 7-aminocephalosporanic acid and 0.58 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 10 ml of acetic acid, and 6.6 grams of tin tetrabromide were added to form a solution. This solution was allowed to react at 50 ° for 2 hours. The reaction mixture was diluted with 10 ml of water, and 28% by weight of aqueous ammonia was added under ice-cooling to adjust the pH of the mixture to 3.8. The crystals thus precipitated in were collected by filtration and dissolved in 10 ml of 50% by weight aqueous methanol solution by adding 28% by weight of aqueous ammonia. A small amount of insoluble matter was removed by filtration, after which the pH of the solution was adjusted to 3.8 with 6 N hydrochloric acid. The crystals thus precipitated were collected by filtration, washed with two 5-ml portions of water and two 5-ml portions of acetone in this order, and then dried to give 1.28 grams (yield 78.2 percent) of 7-amino-3 - [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid. In Example 12, 1.36 grams of 7-aminocephalosporanic acid and 0.60 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 10 ml of acetic acid, and 8.9 grams of pyrophoric acid were added to the suspension, after which the resulting mixture was reacted at 450 g. to 500 for 10 hours. After completion of the reaction, the reaction mixture was poured into 10 ml of ice-water, and its pH was adjusted to 3.8 with 28% by weight of aqueous ammonia. The crystals thus precipitated were collected by filtration, washed with two 5 ml portions of water and two 5 ml portions of acetone in this order, and then dried to give 1.7 grams (yield 70.9 percent) of 7-amino acid. 3- [5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid. Example 13 1.35 grams of 7-aminoCephalosporanic acid and 0.60 grams of 5-mercapto-1-methyl-1H-tetrazole were suspended in 7.0 ml of acetic acid, and 0.93 ml of 10% magic acid (fluorosulfuric acid: antimony pentafluoride = 1: 1 mol) was added to the suspension under ice-cooling, after which the mixture was allowed to react at 30 ° for 3 hours.

After completion of the reaction, the reaction mixture was poured into .35 ml of ice water, and the pH of the resulting solution was adjusted to 3.7 with conc. aqueous ammonia, after which the solution was stirred under ice-cooling for 1 hour. The crystals thus precipitated were collected by filtration, washed with 10 ml of water and 10 ml of acetone in this order, and then dried to give 1.34 grams (yield 82.0 percent) of 7-amino-3- [5- ( Limethyl-1,2,3,4-tetrazolyl) -thiomethyl] -β-cephem4-carboxylic acid.

Example 14 The following compounds of the invention are obtained in yields of 65 to 90% under substantially the same conditions as in Examples 1 to 13 using 7-aminocephalosporanic acid, a suitable thiol compound represented by formula (II), an acid selected from sulfuric acid, pyrophosphoric acid, perchloric acid , chlorosulfuric acid, pyrosulfuric acid, fluorosulfuric acid, "magic acid", FSO3H-ASF5, CF3SO3H ~ SbF5, HZSO4-SO3, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, zinc chloride, zinc (bromide), IV) bromide and a solvent selected from acetonitrile and acetic acid 7-amino-3- [2- (1,3,4-thiadiazolyl) thiomethyl] -α? -Cephem-4-carboxyl-I acid, m.p. 202-204 ° C (dec.), 7-amino-3- [5- (1-sulfomethyl-1,2,3,4-tetrazolyl) thiomethyl] -α-cephem-4-carboxylic acid, m.p. 205-215 ° C (dec.), 7-amino-3- [2- (5-methyl-1,3,4-oxadiazolyl) thiomethyl] -α-cephem-4-carboxylic acid, m.p. 206-207 ° C (dec.), 7-amino-3- [2- (1-methyl-1,3,4-triazolyl) thiomethyl | -E-Cephem-4-carboxylic acid, m.p. 192 ° C (dec.), 7905899-6 A26 7-amino-3 - [(1,3-thiazolylphthiomethyl] -3-cephem-4-carboxylic acid, mp 210 ° C (dec.), 7-amino-3 1- [5- (3-methyl-1,2,4-thiadiazolyl) thiomethyl] -α-cephem-4-carboxylic acid, IR (KBr) cm -1: 1797 (lactam), 7-amino-3- [2- (5-methyl) -1,3,4-triazolyl) thiomethyl-α 4 -Cephem-4-carboxylic acid, mp 214 ° C (dec.), 7-amino-3-[1- (1-carboxymethyl-1,2,3,4- tetrazolyl) thiomethyl-3 3 -Cephem-4-carboxylic acid, mp 188 ° C (dec.), 7-amino + 3-15-[1- (2-N, N-dimethylaminoethyl) -1,2,3,4- Tetrazolyl-thiomethyl-α3-cephem-4-carboxylic acid, mp 15 DEG-35 DEG C. (decomposition) β-amino-3-[1- (1-phenyl-1,2,3,4-tetrazolyl) -thiomethyl] Α-Cephem-4-carboxylic acid, mp 209-210 ° C (dec.), 7-amino-3- [2- (benzoxazolyl) thiomethyl] -α-cephem-4-carboxylic acid, Y mp 210-212 ° C (decomposition), 7-amino-3- [1- (1,2,3-triazolyl) tibmethyl] -α; -cephem-4-carboxylic acid, mp 209 ° C (dec.), 37-amino -3- [2- (Benzimidazolyl) thiomethyl] -β-cephem-4-carboxylic acid, mp> 230 ° C (dec.), * 7-amino-3-propylthiomethyl 1-Å3-cephem-4-carboxylic acid, m.p. > 155 ° C, (decomposition), 7-amino-3-phenylthiomethyl-N-cephem-4-carboxylic acid, m.p. > 235 ° C (dec.), 7-amino-3- [1- (1-ethyl-1,2,3,4-tetrazolyl) thiomethyl] -α-cephem-4-carboxylic acid, m.p. 201-203 ° C (dec.), 7-amino-3- [1- (1-carbamoylmethyl-1,2,3,4-tetrazolyl) thiomethyl] -3-cephem-4-carboxylic acid, m.p. 189 DEG-190.5 DEG C. (decomposition), 7-amino-3- [5-1] - (2-hydroxyethyl) -1,2,3,4-tetrazolyl] thiomethyl-A3-cephem-4-carboxylic acid, 190 DEG-192 DEG. (decomposition), 7-amino-3- (ethoxycarbonylmethylthiomethyl) -α-cephem-4-carboxylic acid, m.p. 208-210 ° C (dec.), 7-amino-3- (carboxymethylthiomethyl) -β-cephem-4-carboxylic acid, m.p. 193-196 ° C (dec.), 7-amino-3- [5-1] - (2-aminoethyl) -1,2,3,4-tetrazolylthiomethyl] -αg-cephem-4-carboxylic acid, m.p. 204-207 ° C (dec.), 7-amino-3-1,5A (1,2,3,4-tetrazolyl) thiomethyl] -E @ -cephem-4-carboxylic acid, IR (KBr) cm-1: 1800 (lactam), 7-amino-3- [2- (5-methyl-1,3,4-thiadiazolyl) thiomethyl] -α-cephem-4-carboxylic acid, m.p. 199-200 ° C (dec.), 7-amino-3- [2- (1,3-pyrimidinyl) thiomethyl-α-cephem-4-carboxylic acid, m.p. 20 ° C (dec.) 7-amino-3- [2- (1H-1,3,4-triazolyl) thiomethyl] -AP-cephem-4-carboxylic acid, m.p. 195 ° C (dec.), 7-amino * 3- (6-hydroxypyridazin-3-ylthiomethyl) -α-cephem-4-carboxylic acid, m.p. 292-295 ° C (dec.), 7-amino-3- (tetrazole-4,5-bipyridazin-6-ylthiomethyl) -β-cephem-4-carboxylic acid, m.p. 245-250 ° C (dec.), 7-amino-3- (1H-4-methyl-5,6-dioxo-4,5-dihydro-1,2,4-triazin-3-ylthiomethyl) -E9-cephem -4-carboxylic acid, m.p. 220-230 ° C (dec.), 79oss99-6 28 7-amino-3-I (2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) thiomethyl {-Û? -Cephem-4-carboxylic acid, m.p. 190 ° C (dec.), 7-1R (K: sr) cm -1 = uc = o 1800, 1720, 1640, 1615, 1540.

Example 15 In 3 ml of anhydrous acetonitrile was suspended 0.29 g of (1R) -7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid 1-oxide and 0.38 g of 5-mercapto-1-methyl-1H- tetrazole, and 0.98 g (0.53 ml) conc. sulfuric acid was added to the resulting suspension under ice-cooling in order to transfer the suspension to a solution. The reaction was carried out at 30 ° C for 1 hour, then the reaction mixture was cooled with ice and added to 6 ml of water at 5-10 ° C, after which the pH of the resulting mixture was adjusted to 3.5 with 28% aqueous ammonia. The precipitated crystals were collected by filtration and then washed with two portions of 1.5 ml of water and two portions of 1 ml of acetone in that order and then dried to give 0.25 g (yield 76.2%) of 7-amino acid. 3-15- (1-methyl-1,2,3,4-tetrazolyl) Liomethyl-α3-cephem-4-carboxylic acid. Melting point: 224-226 ° C (decomposition) IR (mar) to: C = o 1792, 1610, 1520 NMR (D 2 O + CF 3 CO 2 D) ppm values: 3.58 (zu, s, cz-Hz), 3.84 (314, s,; N-CH 3), 4.09 (211, s, c 3 -CH 2), 4.91 (111, d, J = 5 eps, C 6 -H), 5.05 (1H, d, J = 5 cps, C7-H).

Example 16 In 4.7 ml of acetonitrile was dissolved 0.47 g of p-toluenesulfonic acid salt of ethyl 7-aminocephalosporanate and 0.12 g of 5-mercapto-1-methyl-1H-tetrazole, and 0.9 g of trifluoromethanesulfonic acid was added to the obtained the solution and this was allowed to react at 50 ° C for 1.5 hours. The solvent was removed by distillation under reduced pressure, and 5 ml of methylene chloride and 5 ml of water were added to the obtained residue to dissolve it; The pH of the resulting solution was adjusted to 7.0 by the addition of sodium bicarbonate under ice-cooling, and the organic layer was separated, washed with water and then dried over anhydrous magnesium sulfate. To the organic layer thus obtained was added a solution of 0.19 g of p-toluenesulfonic acid monohydrate in 1 ml of methanol, and the solvent was then removed by distillation under reduced pressure. To the obtained residue was added diethyl ether, and the undissolved portion was collected by filtration to give 0.40 g (yield 75.6%) of the p-toluenesulfonic acid salt of ethyl 7-amino-3-i5- (1-methyl-1,2, 3,4-Tetrazolylthiomethyl [α] D-cephem-4-carboxylate, m.p. 115 DEG-222 DEG C. (decomposition). (M) cm @ 1; (1 DEG-1.70 DEG C., 17155 NMR KCDCl3) ppm values: - 1.23 (3H, t J = 6 cps, -CH2-CH3), 2.30 (3H, s, -C6H4-CH3), 3.45 (2H, s, C2-H2), 3.81 ¶3H, s, N-CH 3), 4.30, 4.04 (ZH, ABq J = 10 cps, C 3 -CH 2), 4.95 (2H, m, C 7 -H, -C 6 -H), 7.01, 7.59 (4H, ABq J = 8 cps, CGH4), 8.37 (2H, br, -NH2). ..__.._..._....-.__.

Claims (1)

A process for the preparation of a 7-amino-substituted -amino-3-substituted thiomethyl-α-cephem-4-carboxylic acid represented by the formula $ 1 Rzc-cazsa in COOH wherein R 1 is a hydrogen atom or a C 1-4 alkoxy group; R2 is an amino group or a group represented by the formula III. R \ _ ~ .3 4 s. . 4, C 1 -C 6 NH 4, wherein R 1, R 2 and R 3, which may be the same or R 2 are different, are hydrogen atoms or unsubstituted or substituted aliphatic radicals, alicyclic radicals, aromatic radicals, araliphatic radicals, heterocyclic radicals or acyl groups, 6; :: C = N-, wherein R6 and R7, which may be the same R or of the formula R or different, are hydrogen atoms or unsubstituted or substituted aliphatic radicals, alicyclic radicals, aromatic radicals, araliphatic radicals, heterocyclic radicals or acyl- groups; and R 8 is a residue of a compound of the formula R 8 SH, wherein R 8 is unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, acyl, thiocarbamoyl, alkoxythiocarbonyl, aryloxy-thiocarbonyl, cycloalkyloxythiocarbonyl, amidino or heterocyclic groups; I), wherein the carboxyl group is protected with ester-forming groups.or a salt __- thereof, characterized in that a Cephalosporanic acid represented by the formula 3 is reacted! 7905399-6 RLL-w / Y * Q // Jr-N / cnzx (n) coon wherein R 1 and R 2 are as defined above; X_ is an unsubstituted or substituted acyloxy or carbamoyloxy group; §> Y is: S or F; S- + O; or said compound (II), wherein the carboxyl group is protected with an ester-forming group or a salt thereof, with a thiol compound represented by the formula R8-SH (III) wherein R8 has the meaning given above, or a salt thereof in an organic solvent at a temperature of -20 ° C to 80 ° C in the presence of a protonic acid selected from pyrophosphoric acid, pyrosulfuric acid, sulfuric acids, sulfonic acids or superacids or Lewis acids selected from zinc halides or tin halides.